Dabrafenib (TAFINLAR™ capsule) was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of patients with non-operable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc. USA) for detection of BRAF V600E. Dabrafenib has also been approved by the EMA in the European Union and TGA in Australia for unresectable or metastatic melanoma, and as an adjuvant treatment for melanoma following resection of involved lymph nodes with the BRAF mutation. Other approved indications include anaplastic thyroid cancer and non-small cell lung cancer with the same BRAF mutation.
In November 2015, the FDA also approved the combination of dabrafenib and trametinib for the treatment of metastatic melanoma.
BRAF mutations occur in 50% of melanomas. BRAF inhibitors such as dabrafenib target mutant BRAF and inhibit the MAPK signalling pathway, which mediates cell growth and survival. They are not effective in non-mutant (wild-type) BRAF tumours.
Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumour promotion.
How does dabrafenib work?
- Dabrafenib blocks a critical protein molecule called Mutant B-raf (B-RAF), which is mutated (changed) in up to 50% of patients with melanoma.
- B-RAF is a protein that is part of the cell signalling pathway that controls cell growth in a number of different tissues in the body.
- Mutations that lock the B-RAF protein in an active state can cause excessive signalling in the RAS/RAF/MEK/ERK (MAPK pathway) signalling pathway, leading to uncontrolled growth of melanocytes (pigment cells).
- When the activity of mutant B-RAF is blocked, cancer cells stop growing and die.
Which patients benefit from dabrafenib treatment?
- Dabrafenib is specifically indicated for patients with melanoma whose tumours express a gene mutation called BRAF V600, as detected by an FDA approved atest.
- The BRAF protein produced as a result of this gene mutation has the amino acid (building blocks of protein) glutamate instead of the amino acid valine at position 600.
- Dabrafenib is not indicated for use in patients without the V600 mutation.
- Dabrafenib has proven activity in patients with BRAF V600E and BRAF V600K metastatic melanoma, including those with brain metastases.
Link to key clinical-trial evidence
Dosage and administration
The recommended dose is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal.
What adverse events can dabrafenib cause?
In clinical trials, adverse events were common but rarely led to dose reduction or discontinuation.
Most frequent toxicities (ranging from 15% to 33%) included:
- arthralgia (painful joints)
- pyrexia (fever)
Cutaneous side effects include:
- scaly dry skin
- skin papillomas (benign papules)
- rash (non-specific red skin)
- warty keratosis
- drug-induced vitiligo
- transient acantholytic dermatosis with monotherapy.
Serious adverse events included:
- cutaneous squamous cell carcinomas (9%)
- basal cell carcinomas (4%)
- hyperglycaemia (6%)
- uveitis and iritis (1%)
Dabrafenib can cause fetal harm when administered to a pregnant woman (Pregnancy Category D). The patient should be warned of the potential hazard to the fetus, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.
The safety and effectiveness of dabrafenib have not been established in children.
Hepatic and renal impairment
No formal pharmacokinetic trial in patients with hepatic or renal impairment has been conducted.
Dabrafenib is primarily metabolised by hepatic enzymes CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.
If concomitant use of strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, patients should be monitored closely for adverse reactions or loss of efficacy.
Coadministration of dabrafenib with warfarin, dexamethasone, or hormonal contraceptives, can also result in decreased concentrations and loss of efficacy.
Drugs that alter the pH of the upper gastrointestinal tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic absorption of dabrafenib.
Alleged differences between dabrafenib and vemurafenib
Dabrafenib and vemurafenib are both selective type 1 BRAF inhibitors with proven efficacy in BRAF V600E metastatic melanoma. They share many attributes, including clinical activity and class-defined toxicity; however, differences between the drugs exist.
- Dabrafenib is a more selective inhibitor of BRAF V600E than vemurafenib.
- Dabrafenib has proven intracranial activity, and phase I and II trial data support its clinical efficacy in BRAF V600E and BRAF V600K patients with brain metastases.
- Cutaneous toxicities such as photosensitivity, rash, hyperkeratosis and cutaneous squamous cell carcinoma occur with both drugs but have been reported to occur to a lesser degree with dabrafenib.
- Hepatitis appears to be specific to vemurafenib. It has not been reported in any trials with dabrafenib.
Limitations of dabrafenib and future directions
In patients with BRAFmut metastatic melanoma, dabrafenib confers high response rates and an improved overall survival rate over chemotherapy, with a mild, manageable toxicity profile. However, the duration of benefit is usually brief because of the development of acquired resistance.
Combination therapies targeting multiple components of cell signalling, such as CombiDT (combination of dabrafenib with trametinib [an MEK inhibitor manufactured by GSK and approved by US FDA]), has shown higher response rates and more durable clinical benefit than dabrafenib monotherapy. The combination of dabrafenib and trametinib, Mekinist™, was provisionally approved by the FDA for unresectable and metastatic melanoma with BRAF V600E or V600K mutations, in 2014 with regular approval in November 2015.
As both drugs target the MAPK pathway, the combined blockade may circumvent or delay acquired resistance because of reactivation of the MAPK pathway.
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).